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ScienceWeek
SCIENCEWEEK
ScienceWeek
January 31, 2003
Vol. 7 Number 5
An Online Digest of Research in the Sciences
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It is impossible to express a really new principle in terms of a
model following old laws." -- Max Planck (1858-1947)
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Section 1
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Thematic Issue: Mechanisms of Aging
1. Introduction.
2. Biology of Aging: Puzzles and Problems.
3. Regulation of Life-Span in C. Elegans.
4. Telomeres and Senescence.
5. DNA Repair and Aging.
6. Mitotic Errors and Human Aging.
7. Genomes and Longevities.
Notices and Subscription Information
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Section 2
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1. INTRODUCTION.
GENES, AGING, AND LONGEVITY.
"Why do we age? Is there a program encoded in our genetic
blueprints, secreted deep in the nucleus of each of our cells?
Are we therefore predestined to grow old and die according to a
genetically predetermined plan? Does our lifestyle impact any
such programmed scheme? Absent the common culprits of cancer and
cardiovascular disease, could we live to be 200?...
"Circumscribed life spans are characteristic throughout the
animal kingdom, as they are in humans. The lowly worm C. elegans,
which has proven so vital to the understanding of gene function,
has a life span of only fifteen days; however, mutations induced
in this primitive worm have succeeded in doubling its life span.
The life span of the mouse rarely exceeds two years; that of
rats, four years; of cats, thirty years; of elephants, sixty
years; and of horses, forty years. Bats, with an average life
span of about thirty years, age much more slowly than mice,
although the two species have similar body weights and cell
chemistry (metabolic rates). Humans and virtually all animals
age. Exceptions are those species that continue to grow in size
after reaching adulthood. For example, several fish and reptile
species show no biological age changes. They are not, however,
immortal: They inevitably succumb to disease, predators, or
accidents.
"Laboratory rats fed diets that were sufficient in all
constituents except calories showed retarded growth during the
period of calorie restriction. After their caloric intake was
increased, the rats proceeded to grow to adult size. They
eventually exceeded the normal expected life span for that strain
of rats. They reached about twice the maximum age achieved by
rats whose diets were not interdicted. Of particular interest was
the observation that rats that were initially on the calorie-
restricted diet had an associated delay in the onset of various
tumors and chronic diseases related to aging. Calorie restriction
also was shown to extend the life span of laboratory mice by 50
percent or more; but these mice were less fertile than normal
mice, and were about 30 percent smaller. Similar results have
been noted in chickens, bees, silkworms, and other species. The
prolonging of life was most pronounced when low-calorie diets
were started soon after birth. Removal of the sex glands of
salmon early in their development also has been noted to prolong
their life span.
"Even the surrounding temperature in which animal species live
has been questioned in its relationship to age. Fish raised at
low temperatures have better growth and live longer. In contrast,
rats reared at low room temperatures have a considerable decrease
in their life span from all causes of death -- including, for
some strange reason, cancer.
"Mice raised in a germ-free environment have been shown to have a
longer mean life span, as have rats that have had their spleens
removed early in life. The implication of both of these
experiments is that the body defenses that act against infection
play a role in the aging process.
"That females tend to live longer than males suggests an
influence of the sex hormones. This characteristic is not
confined to the human species: Female spiders, fish, water
beetles, houseflies, chickens, and fruit flies all live longer
than their male counterparts. Yet in some bird species,
especially pigeons, males reputedly live longer than females.
Cats that have been castrated have attained the highest recorded
ages. No equivalent human data exist (fortunately!). Some female
fruit flies that are virgins, born without ovaries, or
sterilized, live longer than their normal female contemporaries.
Virgin mice live longer than spayed females; but the oldest of
all are castrated mice."
Aubrey Milunsky: Your Genetic Destiny. Perseus Publishing 2001,
p.270.
SENESCENCE
"Entropy always wins. Each multicellular organism, using energy
from the Sun, is able to develop and maintain its identity for
only so long. Then deterioration prevails over synthesis, and the
organism ages. Aging can be defined as the time-related
deterioration of the physiological functions necessary for
survival and fertility. The characteristics of aging -- as
distinguished from diseases of aging (such as cancer and heart
disease) -- affect all the individuals of a species.
"Many evolutionary biologists (Medawar 1952; Kirkwood 1977) would
deny that aging is part of the genetic repertoire of an animal.
Rather, they would consider aging to be the default state
occurring after the animal has fulfilled the requirements of
natural selection. After its offspring are born and raised, the
animal can die. Indeed, in many organisms, from moths to salmon,
this is exactly what happens. As soon as the eggs are fertilized
and laid, the adults die. However, recent studies have indicated
that there are genetic components to senescence, and that the
genetically determined life span characteristic of a species can
be modulated by altering genes or diet.
"The maximum life span is a characteristic of the species. It is
the maximum number of years a member of that species has been
known to survive. The maximum human life span is estimated to be
121 years (Arking 1998). The life spans of tortoises and lake
trout are both unknown, but are estimated to be more than 150
years. The maximum life span of a domestic dog is about 20 years,
and that of a laboratory mouse is 4.5 years. If a Drosophila
fruit fly survives to eclose (in the wild, over 90% die as
larvae), it has a maximum life span of 3 months.
"However, a person cannot expect to live 121 years, and most mice
in the wild do not live to celebrate their first birthday. The
life expectancy, the amount of time a member of a species can
expect to live, is not characteristic of species, but of
populations. It is usually defined as the age at which half the
population still survives. A baby born in England in the 1780s
could expect to live to be 35 years old. In Massachusetts during
that same time, the life expectancy was 28 years. This was the
normal range of human life expectancy for most of the human race
in most times. Even today, the life expectancy in some areas of
the world (Cambodia, Togo, Afghanistan, and several other
countries) is less than 40 years. In the United States, a child
born in 1986 can expect to live 71 years if male and 78 years if
female.
"Given that in most times and places, humans did not live much
past 40 years, our awareness of human aging is relatively new. A
65-year-old person was rare in colonial America, but is a common
sight today... In 1900, 50% of American women were dead by age
58. In 1980, 50% of American women were dead by age 81. Thus, the
phenomena of senescence and the diseases of aging are much more
common today than they were a century ago. In 1900, people did
not have the 'luxury' of dying from heart attacks or cancers.
These diseases generally occur in people over the age of 50
years. Rather, people died (as they are still dying in many parts
of the world) from infectious diseases and parasites (Arking
1998). Similarly, until recently, relatively few people exhibited
the more general human senescent phenotype: graying hair, sagging
and wrinkling skin, joint stiffness, osteoporosis (loss of bone
calcium), loss of muscle fibers and muscular strength, memory
loss, eyesight deterioration, and the slowing of sexual
responsiveness. As Shakespeare noted in _As You Like it_, those
who did survive to senescence left the world 'sans teeth, sans
eyes, sans taste, sans everything.'"
Scott F. Gilbert: Developmental Biology 6th Edition, Sinauer
Assoc. 2000, p. 574.
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2. BIOLOGY OF AGING: PUZZLES AND PROBLEMS
Most multicellular organisms exhibit a progressive and
irreversible physiological decline that characterizes what is
called "senescence" -- the aging process. The molecular basis of
this process is unknown, but various mechanisms have been
postulated, including: a) cumulative damage to DNA leading to
genome instability; b) biochemical pathway alterations that lead
to changes in gene expression patterns; c) telomere shortening in
replicative cells; d) oxidative damage to critical macromolecules
by reactive oxygen species; and e) nonenzymatic *glycation of
proteins. Experimental genetic manipulation of the aging process
in multicellular organisms has been achieved in the fruit fly
Drosophila through the overexpression of certain enzymes, and in
the nematode worm C. elegans through alterations in the insulin
receptor pathway, and in both organisms through the experimental
selection of stress-resistant mutants. In mammals, however, the
only intervention that appears to slow the intrinsic rate of
aging is caloric restriction. Most studies of caloric restriction
in mammals have involved laboratory rodents subjected to a long-
term 25 to 50 percent reduction in caloric intake without
essential nutrient deficiency, and the result in these rodents is
a delayed onset of age-associated pathological and physiological
changes and an extension of maximum lifespan. Various mechanisms
have been postulated to explain this result, including increased
DNA repair capacity, altered gene expression, depressed metabolic
rate, and reduced oxidative stress.
M.R. Rose and A.D. Long (University of California Irvine, US)
discuss the biology of aging, the authors making the following
points:
1) Aging is a biological puzzle of long standing, particularly
because it manifests itself over a wide range of biological
systems, tissues and functions. For some time, the outstanding
task has been to find experimental strategies that make sense of
the complexity of aging. Some of the earliest experimental
research on aging was that of Raymond Pearl [3] on the duration
of life in Drosophila during the 1920s. But before 1980, little
progress was made in the study of aging in Drosophila. The
problem was that most of the tools of the genetics trade did not
give useful results. The large-effect mutants studied by Pearl
and colleagues almost always reduced life span. The Drosophila
mutants that enhanced life span most eliminated the reproductive
organs of females [4] , making such mutants of doubtful
relevance. A new crop of mutants that extend Drosophila life
spans have been produced (5), but it is not yet clear whether any
of these will reveal the physiology of normal aging.
2) Most biological research attempts to uncover functional
pathways, whether specific biochemical reactions or large-scale
developmental processes. Such pathways are built by natural
selection, and thus have attributes that are "well-designed",
even though there is no designer. Mutation and other genetic
tricks that modify functional pathways usually impair their
operation, and in so doing they reveal how those pathways
operate. This is why genetics is perhaps the most powerful tool
in the biologist's toolbox. It exposes functions, and teases them
apart.
3) But aging is not a function. Aging can be defined as an
endogenous progressive deterioration in age-specific components
of fitness [6] . It is not actively selected for. It is instead a
secondary effect of the decline in the force of natural selection
with age [7]. From such theory it follows that many loci, and
many biochemical pathways, are expected to produce the
deleterious effects of aging, because it is a secondary side-
effect of normal evolution. Earlier, less definitive work using
selected stocks indicated that many loci contribute to aging in
Drosophila.
References (abridged):
3. Pearl, R. (1922). The Biology of Death. (Lippincott,
Philadelphia).
4. Maynard Smith J. (1958) The effects of temperature and of egg-
laying on the longevity of Drosophila subobscura J. Exp. Biol.,
35:832-842.
5. Lin Y.J., Seroude L. and Benzer S. (1998) Extended life-span
and stress resistance in the Drosophila mutant methuselah
Science, 282:943-946.
6. Rose, M.R. (1991). Evolutionary Biology of Aging. (Oxford
Univ. Press).
7. Hamilton W.D. (1966) The moulding of senescence by natural
selection. J. Theor. Biol, 12:12-45.
Current Biology 2002 12:R311
Related Background:
LONGEVITY IN YEASTS AND ANIMALS
David Gems (University College London, UK) discusses the biology
of the ageing process. A continue question concerning studies of
yeast longevity has been whether experimental results with this
simple organism are applicable to considerations of ageing in
animals. Mutations in several yeast genes can increase the
lifespan of yeast, a unicellular fungus, but it is not clear that
that is of any relevance for understanding the ageing process in
multicellular organisms. Now Tissenbaum and Guarente (2001)
report that the gene _sir-2.1_, a relative of a yeast gene that
controls yeast lifespan, also controls longevity in an animal --
the nematode worm C. elegans. In C. elegans, yeast (C.
cerevisiae), the fruit fly Drosophila melanogaster, and even in
mice, there are many genes that upon mutation increase longevity.
In many cases, the proteins encoded by such genes have
equivalents in higher animals. For example, the adult lifespan of
C. elegans can be tripled as a result of reduced activity of a
signaling pathway resembling that which responds to insulin or
insulin-like growth factor-I (IGF-I) in mammals. But the
important question is whether such genes control ageing in all
animals. Has the biology of ageing been conserved throughout
evolution? Although most types of animals grow old and die, it
does not follow that ageing involves the same processes in all
species. It is possible that in different species the underlying
mechanisms of ageing are different.
Nature 2001 410:154
Related Background:
CELLULAR SENESCENCE, CANCER, AND AGING
A. Krtolica et al (Lawrence Berkeley National Laboratory, US)
discuss cellular senescence, the authors making the following
points:
1) Multicellular organisms have evolved mechanisms to prevent the
unregulated growth and malignant transformation of proliferating
cells. One such mechanism is "cellular senescence", which arrests
proliferation (essentially irreversibly) in response to
potentially oncogenic events. Cellular senescence appears to be a
major barrier that cells must overcome to progress to full-blown
malignancy.
2) Cellular senescence was first described as a process that
limits the proliferation of cultured human fibroblasts
("replicative senescence"). Proliferating cells progressively
lose telomere DNA, and short telomeres, which are potentially
oncogenic, elicit a senescence response. In addition, DNA damage,
expression of oncogenes, and supraphysiological mitogenic signals
also cause cellular senescence. Cellular senescence is controlled
by tumor suppressor genes and seems to involve a checkpoint that
prevents the growth of cells at risk for neoplastic
transformation. In this regard, cellular senescence is similar to
apoptosis. However, whereas apoptosis kills and eliminates
damaged or potential cancer cells, cellular senescence involves a
stable arrest of growth.
3) Cellular senescence is also thought to contribute to aging,
although how it does so is poorly understood. In addition to
arresting growth, senescent cells show changes in function.
Because senescent cells accumulate with age, they may contribute
to age-related declines in tissue function. If so, cellular
senescence may be an example of "antagonistic pleiotropy". Aging
phenotypes are thought to result from the declining force of
natural selection with age. Consequently, traits selected to
maintain early life fitness can have unselected deleterious
effects late in life, a phenomenon termed "antagonistic
pleiotropy". The senescence-induced growth arrest may suppress
the development of cancer in young organisms. The functional
changes, by contrast, may be unselected consequences of the
growth arrest and thus compromise tissue function as senescent
cells accumulate.
Proc. Nat. Acad. Sci. 2001 98:12072
MYTHS CONCERNING AGING
David Concar (New Scientist Magazine) discusses myths concerning
aging, enumerating the myths as follows:
Myth #1: Thanks to modern medicine and scientific advances,
adults today can expect to live into their 70s or 80s, whereas
our ancestors mostly died in early middle age. Reality: The great
increase in average life expectancy at birth in the 20th century
is primarily due to the great reduction in infant mortality. In
actuality, many people in the 18th and 19th centuries lived into
their 70s and 80s.
Myth #2: Given the health improvements and longevity gains of the
20th century, people may soon live routinely to 120 years.
Reality: Again, the main apparent recent changes in longevity are
due to changes in infant mortality rates. Only a small proportion
of the longevity changes came from attacks on killer diseases of
adults. According to death rate statistics, medical science would
have to eliminate every single current common cause of human
death merely to reach a life expectancy of 100.
Myth #3: Researchers can make worms and flies live much longer
than normal, so some kind of treatment that will slow down aging
in humans is inevitable. Reality: Nematode worms and flies are
quite different from humans, and their use as "models" for aging
research is questionable. For the most part, these animals have
been useful in aging research because they have short lifespans,
which makes experiments easier and faster. But this is also
considered the major flaw of research into longevity: such
research is based on animals that lack longevity. The evidence
from aging research on longer-lived species does not support the
idea that scientific manipulation of aging in humans is
inevitable.
Myth #4: Human lifespan can be dramatically extended simply by
ingesting protective antioxidant vitamins to improve the defenses
of the body against free radicals. Reality: This is an overly
optimistic idea. Free radicals are constantly produced in all
biological cells, and virtually all organisms have natural
antioxidants and enzymes to prevent DNA damage and other damage
by free radicals. The problem is that there is no way that
antioxidant supplements can remove all free radicals, and even if
this could be accomplished it would probably damage the workings
of the immune system, which apparently requires free radicals for
some of its pathways. In general, experiments involving the use
of free-radical quenchers that have produced some increase in
longevity in lower animals have produced no increases or even
decreases in mammals.
Myth #5: Semi-starved rats and mice live up to 50 percent longer,
so humans should be able to live to 120 by reducing calorie
intake. Reality: There is no hard evidence for this in humans.
Caloric restriction experiments are now underway with monkeys,
but it will be 10 years before the results are apparent.
Meanwhile, severe caloric restriction in humans produces
debilitation and disease, rather than longevity.
Myth #6: Growth hormone supplements can help forestall aging.
Reality: There is no evidence to support this idea, and in fact
recent evidence suggests that people with lower growth hormone
levels live longer, and that growth hormone supplements have
serious side effects.
But despite the realities above, there are certainly puzzles
that need to be solved by research. Okinawa, a chain of islands
stretching from Japan to Taiwan, has 1.3 million people in a
population with the longest life expectancy on the planet, with
4 times the percentage of centenarians found in Western
countries. Researchers are currently attempting to determine the
factors (diet, lifestyle, genetics, etc.) responsible for
Okinawa's vital statistics.
New Scientist 2001 22 September
ON NEW APPROACHES TO HUMAN AGING
It is probably safe to say that research on the biological basis
of human aging will remain a central interest in the sciences as
long as there is any research at all. However, despite the
general public attention to the subject, it is only during the
past few decades that cell biologists have begun a vigorous
attempt to understand the aging process. A major reason for this
is that the new knowledge provided during the past 40 years by
molecular biology concerning fundamental cellular processes
suggests that an understanding of the biological basis of human
aging is indeed possible.
The cell biologist Leonard Hayflick (University of California San
Francisco, US) first demonstrated in the 1960s that the mortality
of biological cells is either directly or indirectly programmed
in each cell, and that this is an important aspect of the aging
of human tissues (see related background material below).
Hayflick recently presented a provocative essay on the subject,
the author making the following points:
1) The author points out that in the past 100 years life
expectancy at birth in developed countries has increased from
approximately 48 years to 76 years, the same gain that occurred
over the previous 1900 years. But this progress has neither
advanced nor resulted from our understanding of aging. Instead,
it is the control of infectious diseases of the young that
explains the increase in life expectancy during the 20th century.
2) The author suggests that the failure to distinguish between
the diseases of old age and the aging process is widespread even
in the scientific community. The virtual resolution of various
childhood diseases such as poliomyelitis and iron-deficiency
anemia did not increase our knowledge of childhood development.
Similarly, the resolution of the leading causes of death in old
age -- cardiovascular disease, stroke, and cancer -- are unlikely
to advance our knowledge of the aging process.
3) The author suggests that one example of the consequences for
science policy of the failure to distinguish research on age-
associated diseases from research on the fundamental biology of
aging is that "it is virtually impossible to raise funds for
research on aging, because in the minds of policy-makers and the
public no one suffers or dies from it." More than half of the
budget of the US National Institute on Aging is spent on
Alzheimer's disease, yet the elimination of this disease "will
have only a trivial impact on life expectancy and will not
advance our knowledge of the fundamental biology of aging." The
author suggests that greater attention must be given to a
question that is rarely posed: Why are old cells more vulnerable
to disease than young cells?
4) The author concludes: "The resolution of all causes of death
currently written on the death certificates of those older than
65 will result in an increase in life expectancy of only about 15
years. An increase in our knowledge of how age changes occur does
not put a 15-year limit on what is possible."
Nature 2000 403:365
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3. REGULATION OF LIFE-SPAN IN C. ELEGANS.
A nematode worm is an abundant and ubiquitous phylum of
unsegmented roundworms. Caenorhabditis elegans is a small (1 mm)
nematode. It is transparent, hermaphroditic, free-living, and
found in soil. It has a relatively small genome (approximately
19,000 genes), and only a few types of cells in its body. It has
a 16-hr embryogenesis that can be achieved in a petri dish, and
is thus highly suitable for the study of developmental and
behavioral genetics. Although the numbers of described species of
nematodes is only approximately 20,000, estimates of the actual
number range from 40,000 to 10 million. The high estimates are
based on repeated sampling of single marine habitats and are
supported by surveys of terrestrial faunas. Nematodes are also
numerically abundant, attaining millions of individuals per
square meter. C. elegans is therefore a representative of a
diverse and successful group of animals.
N. Arantas-Oliveria et al (University of California San
Francisco, US) discuss regulation of life-span in C. elegans, the
authors making the following points:
1) Killing the germ-line precursor cells, Z2 and Z3, extends the
life-span of C. elegans by approximately 60% (1). This longevity
is not a result of sterility, because removing the entire
reproductive system (germ line and somatic gonad) has no effect
on life-span. In order for germ line-ablated animals to live
longer than normal, they require DAF-12, a nuclear hormone
receptor, and DAF-16, a forkhead-family transcription factor. The
authors found that this effect could be reproduced genetically:
mes-1(bn7) mutants, which lack germ cells, were long lived, as
were glp-1(q158) mutants.(2,3) glp-1 encodes the receptor for a
germ-line proliferation signal that is produced by the distal tip
cells of the somatic gonad (4,5). In glp-1(q158) mutants, Z2 and
Z3 generate only a few germ cells, which then enter meiosis and
differentiate as sperm. In both mutants, life-span extension was
suppressed by a daf-16 null mutation and by ablation of the
somatic gonad precursor cells. Many other mutants with defective
germ-line proliferation were also long lived.
2) The germ-line precursors are stem cells that divide
continuously during development. As development progresses, germ
cells located farthest from the distal tip cells enter meiosis
and then differentiate into sperm (during the L4 stage) or
oocytes (during adulthood), but a pool of proliferating stem
cells is maintained well into adulthood. The authors found that
neither sperm nor oocytes are required for the germ line to
shorten life-span. Previously, fem-3(e1996) mutants, which do not
produce sperm and develop as females, were found to have normal
life-spans. Three additional female mutants, fog-1(q180), fog-
2(q71), and fog-3(q470) (12-14), also had normal life-spans. In
daz-1(tj3) mutants, oocyte precursor cells arrest development at
meiotic prophase and subsequently undergo apoptosis. The life-
spans of daz-1 mutants were similar to those of the wild type .
In addition, germ-line ablation extended the life-span of males,
which do not produce oocytes, to the same extent as for control
hermaphrodites.
3) In summary: The germ line of the nematode Caenorhabditis
elegans influences life-span; when the germ-line precursor cells
are removed, life-span is increased dramatically. The authors
report that neither sperm, nor oocytes, nor meiotic precursor
cells are responsible for this effect. Instead life-span is
influenced by the proliferating germ-line stem cells. These
cells, as well as a downstream transcriptional regulator, act in
the adult to influence aging, indicating that the aging process
remains plastic during adulthood. The authors propose that the
germ-line stem cells affect life-span by influencing the
production of, or the response to, a steroid hormone that
promotes longevity.
References (abridged):
1. H. Hsin and C. Kenyon, Nature 399, 362 (1999).
2. C. Kenyon, J. Chang, E. Gensch, A. Rudner, R. Tabtiang, Nature
366, 461 (1993).
3. S. Strome, P. Martin, E. Schierenberg, J. Paulsen, Development
121, 2961 (1995).
4. F. E. Tax, J. J. Yeargers, J. H. Thomas, Nature 368, 150
(1994).
5. S. T. Henderson, D. Gao, E. J. Lambie, J. Kimble, Development
120, 2913 (1994).
Science 2002 295:502
Related Background Brief:
SIGNALS FROM THE REPRODUCTIVE SYSTEM REGULATE THE LIFESPAN OF C.
ELEGANS. Understanding how the ageing process is regulated is a
fascinating and fundamental problem in biology. The authors
demonstrate that signals from the reproductive system influence
the lifespan of the nematode Caenorhabditis elegans. If the cells
that give rise to the germ line are killed with a laser
microbeam, the lifespan of the animal is extended. The authors
suggest their findings indicate that germline signals act by
modulating the activity of an insulin/IGF-1 (insulin-like growth
factor) pathway that is known to regulate the ageing of this
organism. Mutants with reduced activity of the insulin/IGF-1-
receptor homologue DAF-2 have been shown to live twice as long as
normal, and their longevity requires the activity of DAF- 16, a
member of the forkhead/winged-helix family of transcriptional
regulators. The authors find that in order for germline ablation
to extend lifespan, DAF-16 is required, as well as a putative
nuclear hormone receptor, DAF-12. In addition, the findings
suggest that signals from the somatic gonad also influence
ageing, and that this effect requires DAF-2 activity. The authors
suggest that together their findings imply that the C. elegans
insulin/IGF-1 system integrates multiple signals to define the
animal's rate of ageing. The authors suggest this study
demonstrates an inherent relationship between the reproductive
state of this animal and its lifespan, and may have implications
for the co-evolution of reproductive capability and longevity. H.
Hsin and C. Kenyon: Nature 1999 399:308.
Related Background Brief:
TRANSFORMATION OF THE GERM LINE INTO MUSCLE IN MES-1 MUTANT
EMBRYOS OF C. ELEGANS. Mutations in the maternal-effect sterile
gene mes-1 cause the offspring of homozygous mutant mothers to
develop into sterile adults. Lineage analysis revealed that
mutant offspring are sterile because they fail to form primordial
germ cells during embryogenesis. In wild-type embryos, the
primordial germ cell P4 is generated via a series of four unequal
stem-cell divisions of the zygote. mes-1 embryos display a
premature and progressive loss of polarity in these divisions: P0
and P1 undergo apparently normal unequal divisions and
cytoplasmic partitioning, but P2 (in some embryos) and P3 (in
most embryos) display defects in cleavage asymmetry and fail to
partition lineage-specific components to only one daughter cell.
As an apparent consequence of these defects, P4 is transformed
into a muscle precursor, like its somatic sister cell D, and
generates up to 20 body muscle cells instead of germ cells. The
authors suggest their results demonstrate that the wild-type mes-
1 gene participates in promoting unequal germ-line divisions and
asymmetric partitioning events and thus the determination of cell
fate in early C. elegans embryos. S. Strome et al: Development
1995 121:2961.
Related Background Brief:
A C. ELEGANS MUTANT THAT LIVES TWICE AS LONG AS WILD TYPE. The
authors report they have found that mutations in the gene daf-2
can cause fertile, active, adult Caenorhabditis elegans
hermaphrodites to live more than twice as long as wild type. This
lifespan extension, the largest yet reported in any organism,
requires the activity of a second gene, daf-16. Both genes also
regulate formation of the dauer larva, a developmentally arrested
larval form that is induced by crowding and starvation and is
very long-lived. The authors suggest their findings raise the
possibility that the longevity of the dauer is not simply a
consequence of its arrested growth, but instead results from a
regulated lifespan extension mechanism that can be uncoupled from
other aspects of dauer formation. daf-2 and daf-16 provide entry
points into understanding how lifespan can be extended. C. Kenyon
et al: Nature 1993 366:404.
Related Background:
A POSSIBLE LINK BETWEEN AGING AND GLUCOSE METABOLISM
Insulin is a vital hormone involved in glucose metabolism, and
uncovering the details of the molecular biology of insulin and
its pathways is the focus of much research. K. D. Kimura et al
(Massachusetts General Hospital and Harvard Medical School, US)
report an insulin-receptor-like gene in the small transparent
worm C. elegans that apparently regulates longevity of the
organism. Evidently poor nutritive conditions cause the worm to
halt normal reproductive development and enter a resting state,
and this process is controlled by a family of genes. Mutations in
these genes can cause the resting state to be abnormally provoked
with a resultant increase in the longevity of the organism. The
similarity between the C. elegans insulin receptor and the human
insulin receptor is apparently causing excitement among
researchers specializing in the molecular biology of glucose
metabolism.
Science 1997 277:942
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4. TELOMERES AND SENESCENCE.
SENESCENCE: DOES IT ALL HAPPEN AT THE ENDS?
"Over 60 years ago Barbara McClintock [1902-1992] described the
telomere and suggested that it protected the chromosome from
illegitimate or end-to-end fusion, thus functioning to protect
the genome. Since that time we have discovered that the telomere
is a complex structure composed of both DNA and a growing list of
associated proteins that together serve to regulate the length of
the telomere and, as predicted by McClintock, protect genomic
integrity. In addition to its protective role, the telomere has
also been hypothesized to serve as a molecular clock that tallies
the number of cell divisions and limits further divisions at a
predetermined point. However, the precise role of telomeres in
predicting and limiting cellular lifespan remains a matter of
much debate."
S.A. Stewart and R.A. Weinberg: Oncogene 2002 21:627.
TELOMERASE AND SENESCENCE.
S. E. Artandi et al (Harvard University, US) discuss telomeres
and aging, the authors making the following points:
1) Telomerase, the reverse transcriptase that synthesizes
telomeric repeats, is present at low levels in human tissue stem
cells, progenitor cells, and germ cells, and is undetectable in
the vast majority of adult somatic tissues. Insufficient
telomerase activity and the inability of DNA polymerase to
replicate the extreme ends of chromosomes lead to telomere
attrition with each round of cell division in the setting of
organ renewal with advancing age (1), high-turnover disease
states (2), and passage in culture (3). During human
tumorigenesis, telomerase becomes reactivated by transcriptional
up-regulation of TERT, the catalytic subunit of telomerase (4).
One critical function served by TERT reactivation during cancer
progression is to avert the adverse consequences of telomere
shortening and loss of chromosomal capping function (5). Less
clear, however, is whether the pro-oncogenic activity of
telomerase extends beyond its role in maintaining telomere
function.
2) In human cells, progressive shortening of telomeres
precipitates replicative senescence after 60-80 divisions of
primary human fibroblasts (3) and crisis after extended division
of cells expressing viral oncoproteins. Introduction of
telomerase into primary human cells stabilizes telomeres,
prevents both senescence and crisis, and endows cells with
unlimited proliferative potential. The ability of telomerase to
rescue cells from the adverse consequences of telomere
dysfunction is likely critical for its role in facilitating
malignant transformation of primary human cells and in
maintaining the viability of established cancer cells.
3) In summary: Telomerase is up-regulated in the vast majority of
human cancers and serves to halt the progressive telomere
shortening that ultimately blocks would-be cancer cells from
achieving a full malignant phenotype. In contrast to humans, the
laboratory mouse possesses long telomeres and, even in early
generation telomerase-deficient mice, the level of telomere
reserve is sufficient to avert telomere-based checkpoint
responses and to permit full malignant progression. These
features in the mouse provide an opportunity to determine whether
enforced high-level telomerase activity can serve functions that
extend beyond its ability to sustain telomere length and
function. The authors report the generation and characterization
of transgenic mice that express the catalytic subunit of
telomerase (mTERT) at high levels in a broad variety of tissues.
Expression of mTERT conferred increased telomerase enzymatic
activity in several tissues, including mammary gland,
splenocytes, and cultured mouse embryonic fibroblasts. In mouse
embryonic fibroblasts, mTERT overexpression extended telomere
lengths but did not prevent culture-induced replicative arrest,
thus reinforcing the view that this phenomenon is not related to
occult telomere shortening. Robust telomerase activity, however,
was associated with the spontaneous development of mammary
intraepithelial neoplasia and invasive mammary carcinomas in a
significant proportion of aged females. The authors suggest these
data indicate that enforced mTERT expression can promote the
development of spontaneous cancers even in the setting of ample
telomere reserve.
References (abridged):
1. Hastie, N. D. , Dempster, M. , Dunlop, M. G. , Thompson, A.
M. , Green, D. K. & Allshire, R. C. (1990) Nature (London) 346,
866-868.
2. Rudolph, K. L. , Chang, S. , Millard, M. , Schreiber-Agus, N.
& DePinho, R. A. (2000) Science 287, 1253-1258.
3. Harley, C. B. , Futcher, A. B. & Greider, C. W. (1990) Nature
(London) 345, 458-460.
4. Kim, N. W. , Piatyszek, M. A. , Prowse, K. R. , Harley, C. B.
, West, M. D. , Ho, P. L. , Coviello, G. M. , Wright, W. E. ,
Weinrich, S. L. & Shay, J. W. (1994) Science 266, 2011-2015.
5. Blackburn, E. H. (2000) Nature (London) 408, 53-56.
Proc. Nat. Acad. Sci. 2002 99:8191
Related Background Brief:
TELOMERE REDUCTION IN HUMAN COLORECTAL CARCINOMA AND WITH AGEING.
The authors have hypothesized that end-to-end chromosome fusions
observed in some tumours could play a part in genetic instability
associated with tumorigenesis and that fusion may result from the
loss of the long stretches of G-rich repeats found at the ends of
all linear chromosomes. The authors therefore asked whether there
is telomere loss or reduction in common tumors. The authors
demonstrate that in most of the colorectal carcinomas that they
analyzed, there is a reduction in the length of telomere repeat
arrays relative to the normal colonic mucosa from the same
patient. The authors speculate on the consequences of this loss
for tumorigenesis. The authors also demonstrate that the telomere
arrays are much smaller in colonic mucosa and blood than in fetal
tissue and sperm, and that there is a reduction in average
telomere length with age in blood and colon mucosa. The authors
propose that telomerase is inactive in somatic tissues, and that
telomere length is an indicator of the number of cell divisions
that it has taken to form a particular tissue and possibly to
generate tumors. H.D. Hastie et al: Nature 1991 350:197.
Related Background Brief:
INHIBITION OF EXPERIMENTAL LIVER CIRRHOSIS IN MICE BY TELOMERASE
GENE DELIVERY. Accelerated telomere loss has been proposed to be
a factor leading to end-stage organ failure in chronic diseases
of high cellular turnover such as liver cirrhosis. The authors
report that to test this hypothesis directly, telomerase-
deficient mice, null for the essential telomerase RNA (mTR) gene,
were subjected to genetic, surgical, and chemical ablation of the
liver. Telomere dysfunction was associated with defects in liver
regeneration and accelerated the development of liver cirrhosis
in response to chronic liver injury. Adenoviral delivery of mTR
into the livers of mTR/ mice with short dysfunctional telomeres
restored telomerase activity and telomere function, alleviated
cirrhotic pathology, and improved liver function. The authors
suggest these studies indicate that telomere dysfunction
contributes to chronic diseases of continual cellular loss-
replacement and encourage the evaluation of "telomerase therapy"
for such diseases. K. L. Rudolph et al: Science 2000 287:1253.
Related Background Brief:
TELOMERES SHORTEN DURING AGEING OF HUMAN FIBROBLASTS. The
terminus of a DNA helix has been called its Achilles' heel. To
prevent possible incomplete replication and instability of the
termini of linear DNA, eukaryotic chromosomes end in
characteristic repetitive DNA sequences within specialized
structures called telomeres. In immortal cells, loss of telomeric
DNA due to degradation or incomplete replication is apparently
balanced by telomere elongation, which may involve de novo
synthesis of additional repeats by novel DNA polymerase called
telomerase. Such a polymerase has been recently detected in HeLa
cells. It has been proposed that the finite doubling capacity of
normal mammalian cells is due to a loss of telomeric DNA and
eventual deletion of essential sequences. In yeast, the est1
mutation causes gradual loss of telomeric DNA and eventual cell
death mimicking senescence in higher eukaryotic cells. The
authors demonstrate that the amount and length of telomeric DNA
in human fibroblasts does in fact decrease as a function of
serial passage during ageing in vitro and possibly in vivo. It is
not known whether this loss of DNA has a causal role in
senescence. C.B. Harley et al: Nature 1990 345:458.
Related Background Brief:
CREATION OF HUMAN TUMOR CELLS WITH DEFINED GENETIC ELEMENTS.
During malignant transformation, cancer cells acquire genetic
mutations that override the normal mechanisms controlling
cellular proliferation. Primary rodent cells are efficiently
converted into tumorigenic cells by the coexpression of
cooperating oncogenes. However, similar experiments with human
cells have consistently failed to yield tumorigenic
transformants, indicating a fundamental difference in the biology
of human and rodent cells. The few reported successes in the
creation of human tumor cells have depended on the use of
chemical or physical agents to achieve immortalization, the
selection of rare, spontaneously arising immortalized cells, or
the use of an entire viral genome. The authors demonstrate that
the ectopic expression of the telomerase catalytic subunit
(hTERT) in combination with two oncogenes (the simian virus 40
large-T oncoprotein and an oncogenic allele of H-ras) results in
direct tumorigenic conversion of normal human epithelial and
fibroblast cells. The authors suggest these results demonstrate
that disruption of the intracellular pathways regulated by large-
T, oncogenic ras and telomerase suffices to create a human tumor
cell. W.C. Hahn et al: Nature 1999 400:401.
Related Background:
BIOLOGY OF AGING: ON TELOMERES AND REPLICATIVE SENESCENCE
In a review of cell senescence, the aging of cell cultures, and
the immortalization of mammalian cells, John M. Sedivy (Brown
University, US) makes the following points:
1) Finite replicative lifespan (senescence) of mammalian cells in
culture is a phenomenon that has generated much curiosity since
its description. The obvious significance of senescence to
organismal aging and the development of cancer has engendered a
long-lasting and lively debate about its mechanisms.
2) Three classical observations are usually cited to argue that
in vitro replicative senescence is a phenomenon with biological
significance: a) the correlation of in vitro lifespan with the
age of the donor; b) the correlation of in vitro lifespan with
the average life expectancy of species; and, c) the reduced in
vitro lifespan of cells from patients afflicted with premature
aging syndromes.
3) Two major theories have been used to explain limited
replicative capacity. The first hypothesis invokes the gradual
accumulation of mutations, and the second hypothesis invokes the
existence of a molecular clock (or clocks) that can keep track of
cell divisions. The second theory is now believed to be generally
true.
4) It is known that cell senescence can be overcome, because many
cell lines in common laboratory use are quite obviously immortal.
Rodent cells can overcome senescence spontaneously. Human,
chicken, bovine, and horse cells rarely, if ever, immortalize
spontaneously.
5) Certain viral or biochemical interventions in human cell
cultures can overcome cell senescence, typically by causing 20 to
30 extra population doublings. At the end of this extended
lifespan, there is a decline and death of the culture in 4 to 6
weeks, which has been termed "crisis". Senescent cells, on the
other hand, can be maintained in vitro in a viable non-
proliferative state for very long periods of time (reports of
from 4 to 6 months, and up to 2 years).
6) The author suggests it is amazing that in spite of very long
periods of apparent "immortality", the senescent program in cells
remains intact in cells in which senescence has been overridden,
so that on removal of the overriding agent, the program is
capable of establishing rapid growth arrest.
7) The current prevailing hypothesis for the nature of the
molecular clock involved in cell senescence is the attrition of
telomeres. Germ cells, and some key stem cells, are known to
express telomerase catalytic activity, whereas the majority of
somatic cells lack it. Murine (mouse) embryonic stem cells
express telomerase and are functionally immortal, and elimination
of telomerase eventually results in loss of proliferation.
8) The author proposes that immortalization of human cells
requires a bypass of both cell senescence and crisis, whereas in
rodent cells cell crisis does not exist and culture lifespan is
limited only by senescence.
9) Evidence indicates that, at least in human cells, telomere
length appears to be linked critically to the triggering of
senescence. The author suggests that although it remains to be
rigorously demonstrated, this strongly implies that activation of
telomerase can result in one-step immortalization. In conclusion,
the author states the two most significant questions in this
field: a) Does cell senescence limit organismal lifespan? And, b)
Is telomerase expression necessary for cancer progression in
vivo?
Proc. Nat. Acad. Sci. 1998 95:9078
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5. DNA REPAIR AND AGING.
ON DNA INTEGRITY
"From its very beginning, life has faced the fundamental problem
that the form in which genetic information is stored is not
chemically inert. DNA integrity is challenged by the damaging
effect of numerous chemical and physical agents, compromising its
function. To protect this Achilles heel, an intricate network of
DNA repair systems has evolved early in evolution. One of these
is nucleotide excision repair (NER), a highly versatile and
sophisticated DNA damage removal pathway that counteracts the
deleterious effects of a multitude of DNA lesions, including
major types of damage induced by environmental sources. The most
relevant lesions subject to NER are cyclobutane pyrimidine dimers
(CPDs) and (6-4) photoproducts (6-4PPs), two major kinds of
injury produced by the short-wave UV component of sunlight. In
addition, numerous bulky chemical adducts are eliminated by this
process. Within the divergent spectrum of NER lesions,
significant distortion of the DNA helix appears to be a common
denominator. Defects in NER underlie the extreme photosensitivity
and predisposition to skin cancer observed with the prototype
repair syndrome xeroderma pigmentosum (XP). Seven XP
complementation groups have been identified, representing
distinct repair genes XPA-G."
L. Wouter et al: Genes and Development 1999 13:768
PREMATURE AGING IN MICE DEFICIENT IN DNA REPAIR AND TRANSCRIPTION
J. de Boer et al (Erasmus University, NL) discuss DNA damage and
aging, the authors making the following points:
1) DNA damage, particularly oxidative lesions derived from normal
metabolism, is thought to contribute to aging, but the mechanisms
involved remain obscure (1-4). To counteract the effects of DNA
damage, an intricate network of DNA repair pathways has evolved
(5). One important pathway is nucleotide excision repair (NER),
which removes helix-distorting damage, including major
ultraviolet (UV)-induced lesions, bulky chemical adducts, and
some forms of oxidative damage. Xeroderma pigmentosum (XP)
patients show the consequences of inherited defects in NER: sun
(UV) hypersensitivity, cancer predisposition, accelerated aging
of the skin, and, frequently, neurodegeneration.
2) Of the seven XP genes (XPA-G), XPB and XPD are exceptional
because different mutations in these genes also cause Cockayne
syndrome (CS) and a photosensitive form of the brittle hair
disorder trichothiodystrophy (TTD). TTD and CS are characterized
by postnatal growth failure, progressive neurological
dysfunction, impaired sexual development, skeletal abnormalities,
and a strongly reduced life expectancy, but not cancer
predisposition. A clue to the intriguing clinical heterogeneity
linked with XPB and XPD mutations came with the discovery that
these genes encode DNA helicase subunits of the transcription
factor IIH (TFIIH) complex, which have dual functions: local
opening of the DNA around a lesion during NER and opening of the
promoter DNA during transcription initiation . Thus, XPB and XPD
mutations may not only compromise NER, causing photosensitivity,
but may also affect transcription. To obtain insight into the
complex pathophysiology of TTD, the authors generated mice
carrying an XPD point mutation [Arg722Trp (R722W)] found in TTD
patients. TTD mice displayed many features of the human disease
and partial defects in transcription and repair. The authors now
report that TTD mice develop premature aging features caused by
DNA damage.
3) In summary: One of the factors postulated to drive the aging
process is the accumulation of DNA damage. The authors provide
strong support for this hypothesis by describing studies of mice
with a mutation in XPD, a gene encoding a DNA helicase that
functions in both repair and transcription and that is mutated in
the human disorder trichothiodystrophy (TTD). TTD mice were found
to exhibit many symptoms of premature aging, including
osteoporosis and kyphosis, osteosclerosis, early greying,
cachexia, infertility, and reduced life-span. TTD mice carrying
an additional mutation in XPA, which enhances the DNA repair
defect, showed a greatly accelerated aging phenotype, which
correlated with an increased cellular sensitivity to oxidative
DNA damage. The authors hypothesize that aging in TTD mice is
caused by unrepaired DNA damage that compromises transcription,
leading to functional inactivation of critical genes and enhanced
apoptosis.
References (abridged):
1. G. M. Martin, S. N. Austad, T. E. Johnson, Nature Genet. 13,
25 (1996).
2. M. E. Dolle, et al., Nature Genet. 17, 431 (1997).
3. F. B. Johnson, D. A. Sinclair, L. Guarente, Cell 96, 291
(1999).
4. T. B. Kirkwood and S. N. Austad, Nature 408, 233 (2000).
5. J. H. J. Hoeijmakers, Nature 411, 366 (2001).
Science 2002 296:1276
Related Background Brief:
RAPID ACCUMULATION OF GENOME REARRANGEMENTS IN LIVER BUT NOT IN
BRAIN OF OLD MICE. Somatic mutations have long been considered a
possible cause of aging. To directly study mutational events in
organs and tissues of aging mammals, the authors generated a
transgenic mouse model that harbors lacZ reporter genes as part
of chromosomally integrated plasmids. Using this model, the
authors determined spontaneous mutant frequencies and spectra in
mouse liver and brain as a function of age. In the liver, mutant
frequencies increased with age from birth to 34 months; in the
brain, an increase was observed only between birth and 4-6
months. Molecular characterization of the mutations showed that a
substantial portion involved genome rearrangement events, with
one breakpoint in a reporter gene and the other in the mouse
flanking sequence. In the liver, these genome rearrangements did
not increase with age until after 27 months, when they increased
rapidly. In brain, the frequency of genome rearrangements was
lower than in liver and did not increase with age. M.E. Dolle et
al: Nat Genet 1997 17:368.
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6. MITOTIC ERRORS AND HUMAN AGING.
MISREGULATION OF MITOSIS AND HUMAN AGING
The idea that human aging is controlled by genes is not the end
but the beginning of research: Does the aging process involve one
gene, or a fixed group of specific genes, or groups of various
genes at different times and in different individuals?
The term "messenger RNA" refers to the ribonucleic acid molecule
transcribed from DNA that carries the coded information
specifying the sequence of amino acids in a protein. Since the
various messenger RNAs present in any cell can be isolated and
identified, the population of present messenger RNAs can be used
to establish a profile of the active genes of that cell.
Fibroblasts are a type of connective tissue cell secreting
structural proteins such as collagen, the proteins forming a
matrix in which the fibroblasts become embedded. These cells can
be easily obtained from skin, and they can be easily cultured
outside the body.
Progeria (Hutchinson-Gilford disease; Hutchinson-Gilford
syndrome; premature senility syndrome) is a condition of
precocious aging, with onset at birth or early childhood, the
condition characterized by growth retardation, a senile
appearance with dry wrinkled skin, early occurrence of
*atherosclerosis in blood vessels, and premature death (usually
before the age of 20) due to coronary artery disease. The disease
is apparently genetic, but the details of the etiology are not
clear.
In this context, the term "phenotype" refers to the specific
individuality of an organism as determined by the interaction
during development between its genetic constitution (genotype)
and the environment.
In this context, the term "mitosis" refers to the entire cell
division phase of the cell cycle, with "cell cycle" referring to
the entire life history of a single cell from mitosis to mitosis,
including the sequence of intervening phases.
In this context, the term "postmitotic cells" refers to cells
that normally do not undergo mitosis once they have fully
differentiated (e.g., neurons and muscle cells).
D.H. Ly et al (4 authors at 2 installations, US) report an
analysis of aging correlates in human genetic profiles, the
authors making the following points:
1) The authors measured messenger RNA levels in actively dividing
fibroblasts isolated from young, middle-age, and old-age humans
and humans with progeria. Messenger RNA levels were analyzed with
high-density *oligonucleotide arrays containing probes for more
than 6000 known human genes.
2) The authors report their results suggest that an altered
expression profile of genes involved in mitosis occurs with age,
and that these changes result in increased rates of *somatic
mutation, leading to numerical and structural *chromosome
aberrations and mutations that manifest themselves as an aging
phenotype.
3) The authors suggest that these chromosome pathologies, which
begin to occur in dividing cells relatively early in life (but in
the postreproductive stage), may lead to misregulation of key
structural, signaling, and metabolic genes associated with the
aging phenotype, such as the apparent misregulations
characteristic of *osteoporosis, *Alzheimer's disease,
*arthritis, etc. Misregulation of this sort is expected to
increase in each round of cell division, and it may be propagated
to other normal mitotic cells (e.g., *leukocytes, *epithelial
cells, *glial cells, etc.) and postmitotic cells (e.g., neurons,
muscles, etc.) through changes in the *extracellular matrix and
oxidized fatty acid derivatives that affect signaling pathways.
Aging, the authors suggest, may therefore occur gradually and in
mosaic patterns, rather than as a uniform phenomenon
characteristic of cancerous growth (which is clonal -- deriving
from a single mutated progenitor cell).
4) The authors conclude: "Additional studies are required before
we can understand the aging process in complex organisms, both in
mitotic and postmitotic tissue, but the studies reported here
highlight important mechanisms that may contribute to aging and
age-related problems."
Science 2000 287:2486
Notes:
... ... *atherosclerosis: "Arteriosclerosis" is a generic term
for several diseases in which the arterial wall becomes thickened
and loses elasticity, and "atherosclerosis" is a form of
arteriosclerosis characterized by patchy thickening (atheroma) in
the subintimal layer (i.e., immediately below the innermost layer
[intima]) of medium and large arteries, the thickening capable of
reducing or obstructing blood flow.
... ... *oligonucleotide arrays: (DNA microarrays) DNA
microarrays are chips containing hundreds or thousands of gene
snippets laid out in precise arrays that provide rapid snapshots
of the expression of whole suites of genes. The general method in
microarray analysis is to a) isolate messenger RNAs (mRNAs)
produced by a genome; b) convert mRNA into complementary DNA
(cDNA); c) add a fluorescent tag to the cDNA for tracking
purposes; d) wash a solution of tagged cDNAs over a DNA
microarray chip. Each DNA snippet on the chip will bind the cDNA
from the corresponding gene, and by measuring the fluorescences
arrayed on the chip, the profile of gene expression is revealed.
... ... *somatic mutation: In general, a mutation occurring in
non-germ cells, which means the mutation is not transmitted to
the next generation of individuals (but is transmitted to the
next generation of cells of that type).
... ... *chromosome: In cells with chromosomes, the chromosomes
are the physical structures into which DNA is organized and on
which genes are carried.
... ... *osteoporosis: A generalized progressive diminution of
bone density (bone mass per unit volume) that causes skeletal
weakness. The ratio of mineral to organic elements is unchanged.
The major clinical manifestations of osteoporosis are bone
fractures resulting from a reduction below the fracture threshold
of the amount of bone available for mechanical support.
... ... *Alzheimer's disease: There are various forms of dementia
produced by various causes. Alzheimer-type dementia (Alzheimer's
disease) is apparently related to what appear to be specific
cellular and histological degenerative processes, with loss of
cells from several specific brain areas, the brain showing
moderate to marked atrophy. Memory loss is the most prominent
early symptom.
... ... *arthritis: In general, inflammation of a joint or a
state characterized by inflammation of joints.
... ... *leukocytes: White blood cells, of which there are
various types.
... ... *epithelial cells: In animals, "epithelial cells" compose
the cell layers that form the interface between a tissue and the
external environment, for example, the cells of the skin, the
lining of the intestinal tract, and the lung airway passages.
... ... *glial cells: Cells of the central and peripheral nervous
system that metabolically support neurons. Such cells also
produce the multiple membrane layers called myelin and enfold
certain nerve cell axons with it.
... ... *extracellular matrix: In general, the extracellular
matrix is a layer consisting mainly of proteins and
glycosaminoglycans that form a sheet underlying endothelial and
epithelial cells. The molecular constituents of the matrix are
secreted by cells in the vicinity. Endothelial cells are the
cells that line blood vessels.
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7. GENOMES AND LONGEVITIES
AGING, LIFESPAN, AND SENESCENCE
Our knowledge of the basis of senescence of cells, tissues, and
organisms (including humans) has entered a new phase in recent
decades because of the new vistas opened by molecular biology.
Model systems have started to provide insights, and one important
approach has been the identification of genes that determine the
lifespan of an organism. The very existence of genes that when
mutated can extend lifespan suggests to many researchers that one
or a few processes may be critical in aging, and that a slowing
of these processes may slow aging itself.
In a short review of current research in the molecular biology of
aging and lifespan, L. Guarente et al make the following points:
1) In the budding yeast Saccharomyces cerevisiae, aging results
from the asymmetry of cell division, which produces a large
mother cell and a small daughter cell arising from the bud. Much
of the macromolecular composition of the daughter cell is newly
synthesized, whereas the composition of the mother cell grows
older with each cell division. It has been shown that mother
cells of this yeast species divide a relatively fixed number of
times, and exhibit a slowing of the cell cycle, cell enlargement,
and sterility. Analysis of *ribosomal DNA in old cells reveals an
accumulation of *extrachromosomal ribosomal DNA of discrete
sizes, apparently representing a cumulative fragmentation of
chromosomal ribosomal DNA. The authors suggest it will be of
great interest to assess the generality of this process as an
aging mechanism.
2) In Caenorhabditis elegans, the *neurosecretory system
regulates whether animals enter the reproductive life cycle or
arrest development at a primitive *diapause stage. Developmental
arrest is apparently induced by a *pheromone and involves
behavioral and morphological changes in many tissues of the
animal, with the lifespan becoming 4 to 8 times longer than that
of the normal 3-week lifespan of fully developed animals.
Declines in pheromone concentration induce recovery to
reproductive adults with normal metabolism and lifespan. Genes
that regulate the function of the C. elegans diapause and the
neuroendocrine aging pathway have been identified, and at least
one of these genes codes for an *insulin-like receptor apparently
involved in metabolism. The authors suggest that if the
association of longevity and diapause is general, it is possible
that *polymorphisms in the human insulin receptor-signaling
pathway genes and related gene *homologues may underlie genetic
variation in human longevity.
3) In plants, there is a large range of lifespans in the various
plant kingdoms. Certain tree species live for well over a
century, whereas other plants complete their life cycle in a few
weeks. The "yellowing" of leaves is often referred to in the
plant literature as leaf senescence or the "senescence syndrome"
-- referring to the process by which nutrients are mobilized from
the dying leaf to other parts of the plant to support their
growth. The senescence syndrome is characterized by distinct
cellular and molecular changes, with the chloroplast the first
part of the cell to undergo disassembly (producing the
"yellowing"). In many plant species, certain hormones can either
enhance or delay senescence. Although the genes that are
expressed during the plant senescence syndrome (as well as ways
to manipulate such senescence) have been identified, much remains
to be done to understand the molecular basis of aging in plants.
For example, nothing is known about the signal transduction
pathways that lead to altered gene expression during senescence,
or how plant hormones such as *cytokinin influence senescence.
But there are now many tools to explore this process. The authors
conclude: "It remains to be seen whether common mechanisms link
the aging process in diverse organisms."
Proc. Nat. Acad. Sci. 1998 95:11034
Notes:
... ... *ribosomal DNA: A ribosome (not to be confused with
riboZYME) is a small particle, a complex of various ribonucleic
acid component subunits and proteins that functions as the site
of protein synthesis. The term "ribosomal DNA" refers to the gene
or genes that code for the RNA in ribosomes. In other words, the
term "ribosomal DNA" does not refer to any DNA in ribosomes
(there is no DNA in ribosomes).
... ... *extrachromosomal: In general, this refers to anything
outside of chromosomes, and in this case to DNA fragments
unincorporated into chromosomal DNA.
... ... *neurosecretory system: In general, all neural systems
contain both neurons that themselves secrete chemical messengers
and neurons that signal special secretory cells to secrete
chemical messengers. A neurosecretory pathway is a delineated
signaling system that involves such a resultant secretion.
... ... *diapause: In general, this refers to any programmed
period of suspended development in invertebrates.
... ... *pheromone: In general, a chemical substance which, when
released into an animal's surroundings, influences the
development or behavior of other individuals of the same species.
... ... *insulin: A protein hormone that promotes uptake by body
cells of free glucose and/or amino acids, depending on target
cell type.
... ... *polymorphisms: A genetic polymorphism is a naturally
occurring variation in the normal nucleotide sequence of the
genome within individuals in a population. Variations are denoted
as polymorphisms only if they cannot be accounted for by
recurrent mutation and occur with a frequency of at least about 1
percent.
... ... *homologues: In general, the term "homologous" means
having the same structure. But the term has special uses in
genetics and evolution biology.
... ... *cytokinin: A group of plant growth substances. They are
chemically identified as derivatives of the purine base adenine.
They stimulate cell division and determine the course of
differentiation. They work synergistically with other plant
hormones called "auxins".
Related Background:
CELLULAR AGING: DONOR AGE AND CELLULAR REPLICATION LIFESPAN
Fibroblasts are a type of connective tissue cell, secreting
structural proteins such as collagen, the proteins forming a
matrix in which the fibroblasts become embedded. These cells can
be easily obtained from skin, and they can be easily cultured
outside the body. Normal human fibroblasts have a finite
replicative lifespan in vitro (i.e., they divide a finite number
of times), and this has been postulated to be a cellular
manifestation of aging of the human organism. Several studies
have indeed shown an inverse relationship between donor age (the
age of the persons from which cultured cells are derived) and
fibroblast culture replicative lifespan. But in all cases the
correlation was weak, and with few exceptions the health status
of the donors was unknown. Thus, the relationship between the
replicative lifespan and the age of the donor from which the
cells are derived has remained equivocal (*Note #1).
V.J. Cristofalo et al report a study of the replicative lifespan
of 124 skin fibroblast cell lines established from donors of
different ages. All donors were medically examined and were
declared "healthy" (according to Baltimore Longitudinal Study of
Aging protocols) at the time the biopsies were taken. The authors
report that both long- and short-lived cell lines were observed
in all age groups, but no significant correlation between the
proliferative potential of the cell lines and donor age was
found. A comparison of multiple cell lines established from the
same donors at different ages also failed to reveal any
significant trends between proliferative potential and donor age.
The authors suggest their results clearly indicate that if health
status and biopsy conditions are controlled, the replicative
lifespan of fibroblasts in culture does not correlate with donor
age.
Proc. Nat. Acad. Sci. 1998 95:10614
Notes:
... ... *Note #1: The possibility that the process of cell aging
and death is under genetic control was first suggested by Leonard
Hayflick in 1961. Hayflick reported that normal human fibroblasts
apparently have an intrinsic limit to the number of times they
can proliferate, with human fibroblasts removed from an embryo
and grown in culture dividing approximately 50 times before they
deteriorate and die. In contrast, human fibroblasts removed from
adults multiply only 15 to 30 times before dying. Also,
fibroblasts removed from young children suffering from Werner's
syndrome (a rare disease that causes premature aging) divide only
2 to 10 times in culture. Further evidence for a relationship
between aging and the replicative capacity of cells was provided
by the discovery that the number of replications in culture is
apparently related to the lifespan of organism. For example,
cultured cells of the Galapagos tortoise, whose maximum life span
is approximately 175 years, divide more than 100 times in
culture, whereas cells from the mouse, whose maximum life
expectancy is only a few years, divide fewer than 30 times in
culture. The correlation roughly holds for other species as well.
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